Helicobacter pylori (hereinafter sometimes referred to as H. pylori) is a Gram negative bacterium isolated from tunica mucosa ventriculi of a patient with active chronic gastritis (Warren, J. R. & Marshall, B. J. Lancet i, 1273-1275, 1983). H. pylori is a 0.5 .mu.m wide, 3-5 .mu.m long Gram negative spirillar bacterium having several flagella and flagella sheaths at one pole or both poles. H. pylori grows under the microaerophillic environment, cannot grow under the aerobic conditions and grows poorly under the anaerobic conditions. It grows at 37.degree. C. and scarcely grows at not higher than 25.degree. C. and not lower than 42.degree. C. The bacterium is notably characterized in that it evidently produces urease (Mobley, H. L. et al., Clin. Microbiol., 26, 831-836, 1988).
H. pylori is present in the mucous layer in the tunica mucosa ventriculi epithelium of humans and swims in the viscous mucous layer using peculiar flagella that the bacterium has. H. pylori specifically resides in the cortical layer of the epithelium ceils and the crevice therein, which provide the most comfortable living environment where gastric acidity is neutral, and lives by utilizing hemin, urea and so on (Hazell, S. L., Adrian, L., J. Infect. Dis., 153, 658-663, 1986).
As to the mechanism of the onset of diseases caused by H. pylori, mucous membrane disorder concept (Hazell, S. L., Adrian, L., J. Infect. Dis., 153, 658-663, 1986), leaking roof concept (Goodwin C.S., Lancet ii, 1467-1469, 1988) and gastrin link concept (Levi, S. et al., Lancet i, 1167-1168, 1989) have been proposed.
The mucous membrane disorder caused by H. pylori is mostly ascribed to a strong urease activity (Hazell, S. L., Adrian, L., J. Infect. Dis., 153, 658-663, 1986). The urea present in the gastric juice is decomposed by the urease of H. pylori to produce a large amount of ammonium and carbon dioxide. The ammonium concentration in the gastric juice is significantly high in the group that tested positive to H. pylori and histological epitheliocyte disorder and increased ulcer coefficient have also been reported from a test where ammonium was orally administered to rats (Murakami, M. et al., Clin. Gastroenterol., 12 (Suppl. 1), S104-109, 1990). Also, there is a report on reduced amounts of PAS (periodic acid schiff)-positive mucosal juice in the tunlea mucosa ventriculi of the patients who tested positive to H. pylori, suggesting possible degradation in the tunica mucosa ventriculi-protective activity due to the decomposition of mucosal juice by the protease of H. pylori (Nakajima, M. et al., Drug Investigation, 2 (Suppl. 1), 60, 1990). It has been further reported that leukotriene B4 activity is high in the tunica mucosa ventriculi where prominent H. pylori-positive leukocyte infiltration is observed (Uchida, T. et al., Therapeutic Research, 12, 85-90, 1991) and that the mucous membrane disorder is caused by the action of phospholipase A2 on bile acid which flows reversely into the stomach. In 1988, Leunk et al. reported the presence of a cytovacuolating toxin in the supernatant of H. pylori culture. The toxin was isolated and purified by Cover et al (Cover, T. L. & Blaser, M. J., J. Biol. Chem. 267, 10570-10575, 1992). There are reports on the toxin that it delays cure of ulcer by hindering the rotation of cells near the ulcer (Chang, K. et al., Gastroenterology, 104 (Suppl.), A52, 1993) and that it acts synergistically with ammonium on cytovacuolation (Sommi, P. et al., Gastroenterology, 104 (Suppl.), A196, 1993). In recent years, disorder of tunica mucosa ventriculi, which is caused by acetoaldehyde produced in the stomach by the alcohol dehydrogenase activity possessed by H. pylori (Salmela, K. S. et al., Gastroenterology, 105, 325-330, 1990), monochloramine produced in the presence of ammonium (Saida, H. et al., Nihon Shokakibyo Gakkai Zasshi 90, 1949, 1993) and interleukin 8 (Crowe, S. E. et al., Gastroenterology, 104, A687, 1993) have been drawing attention.
With regard to the relationship between peptic ulcer and H. pylori, the involvement of H. pylori has been strongly suggested in view of the very high segregation frequency of H. pylori, particularly in duodenal ulcer, and infection with H. pylori is considered to be deeply concerned with prolonged cure and recurrence of peptie ulcer (see, for example, Raws EAJ, et al., Gastroenterology, 94, 33-40, 1988).
With regard to the relationship between gastritis and H. pylori, the causality has been suggested based on oral infection tests in human (Morris, A. & Nicholoson, G. Am., J. Gastroenterology, 82, 192-199, 1987, Marshall, B. J. et al., Med. J. Aust., 142, 436-439, 1985). The segregation frequency of H. pylori from gastritis is high and the correlation between the cell number of H. pylori, and the increase in neutrophilic leukocytes (which is an index of activeness of gastritis) and the degree of clinical symptoms accompanied by infiltration of lymphocyte has been confirmed. Moreover, development of gastritis in vestibulum of stomach with flare and erosion has been endoscopieally observed in animal tests using Japanese monkeys (Shuto, R. et al., Infect. Immun., 61, 933-939, 1993).
The number of reports on the onset of stomach tumor, which begins with persistent infection of H. pylori via atrophic gastritis and intestinal metaplasia is recently on the rise. In 1991, Parsonnet et al. determined the IgG antibody titer of anti-H. pylori using a serum preserved for about 25 years and found a strong correlation between stomach tumor and patients having the antibody. It has been also found, by epidemiological studies, that morbidity of and death from stomach tumor are high in the area where H. pylori antibody positive ratio is high (Parsonnet, J. et al., N. Engl. J. Med., 325, 1127-1131, 1991).
The treatment of stomach ulcer and duodenal ulcer has made a remarkable progress over the recent years. However, the problems remain that they are susceptible to recurrence when drugs therefor are reduced or withdrawn and that an intractable ulcer having resistance to drugs may be developed. With the prevailing indication of the involvement of H. pylori in stomach and duodenal ulcers, eradication of H. pylori by the administration of drugs having antibacterial activity against H. pylori has become the target of investigation (Chiba, N. et al., Am. J. Gastroenterology, 87, 1716-1727, 1992).
The antibacterial activity against H. pylori is particularly prominent in amoxicillin and clarithromycin from among the antibacterial drugs. While the antibacterial activity can be also found in such antiprotozoals as metronidazole and tinidazole, resistance to these drugs is known to be acquired at a rather early stage. Of the antiulcer drugs, proton pump inhibitors such as omeprazole show weak antibacterial activity, whereas H2 receptor antagonists such as cimetidine, ranitidine and famotidine fail to show such activity. The drugs having an antibacterial activity exhibit only weak clinical effects by single administration. Therefore, administration of plural antibacterial drugs, dual therapy concurrently using a bismuth preparation and an antibacterial drug, or triple therapy using a bismuth preparation and two antibacterial drugs has been tried. Yet, these therapeutic methods rather frequently cause side effects such as diarrhea and abdominal distension.
There are many reports supporting the effectiveness of the eradication of H. pylori and they agree on a conclusion that the eradication resulted in cure of intractable ulcer and suppression of ulcer recurrence.
Raws et al. achieved 88% eradication by the concurrent use of three drugs of bismuth subcitrate, amoxicillin and metronidazole and 6% recurrence ratio one year thereafter (Raws EAJ, et al., Gastroenterology, 94, 33-40, 1988). Moreover, Graham et al. reportedly used three drugs of bismuth subcitrate, tetracycline and metronidazole along with the treatment using ranitidine and achieved eradication in 89% of the ulcer cases and recurrence ratio after one year of 12% in duodenal ulcer and 13% in stomach ulcer, which ratios being remarkably lower than the recurrence ratios of 95% and 74% after the treatment solely with ranitidine (Graham, D. Y. et al., Shok aki naishikyo, Vol. 4, 429-440, 1992). A therapy by the concurrent use of a proton pump inhibitor and an antibacterial drug has been tried in recent years and ulcer recurrence-preventive effect to the same degree as that achieved in the concurrent use of three antibacterial drugs was reportedly obtained (Fujioka, T. et al., Nihon Rinsyo, Vol. 51, 3255-3260, 1993).
Some report says that administration of an antibacterial drug for eradicating H. pylori to a patient with intractable ulcer, who failed to cure with H2 receptor antagonists, resulted in cure of the ulcer, thus suggesting a potential use of the administration as a treatment method as well as for the prevention of recurrence. As stated in the foregoing, the usefulness of eradicating H. pylori is evident, though many problems remain to be solved before complete eradication is achieved. For example, long-term administration of bismuth preparation, which is useful for the eradication of H. pylori, is not possible, due to diarrhea, nausea and side effects on central nervous system it causes, bismuth subcitrate is not approved as an antiulcer drug in Japan, side effects caused by the multiple drug therapy are frequently found, antibacterial drugs used for the multiple drug therapy amounts high, usable time periods of the antibacterial drugs have not been established yet and re-infection after the eradication of H. pylori is found. In view of the problems as described, an antiulcer drug having a strong selective antibacterial action on H. pylori and less side effects is desired. It is needless to say that a drug having an antibacterial action only against H. pylori, and gastric acid secretion suppresslye action as well, is desirable from the aspect of ulcer curing.
Japanese Patent Unexamined Publication Nos. 209809/1990, 8523/1991, 48680/1991, 52887/1991, 52812/1991 and International Publication No. WO92/12976 disclose compounds having antibacterial activity against Helicobacter pylori. A similar compound has been disclosed in Japanese Patent Unexamined Publication No. 100449/1994 which was published after the priority date of the present invention. A compound having more excellent activities than these compounds is demanded.